THE MECHANISMS OF AUTOIMMUNE RESPONSE INITIATION IN MULTIPLE SCLEROSIS

多发性硬化症中自身免疫反应的启动机制

• 批准号: 7273519
• 负责人: Silva Markovic-Plese
• 金额: $ 16.56万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7273519
• 关键词: Affect; Age; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Process; Autoimmune Responses; Blood Circulation; CD28 gene; CD4 Positive T Lymphocytes; CNS Demyelinating Autoimmune Diseases; Cell Death; Cells; Characteristics; Chronic; Complex Mixtures; Cytokine Gene; Development; Disease; Environment; Etiology; Event; Exhibits; Frequencies; Gene Expression; Goals; Growth; Human; Inflammatory; Ligands; Molecular; Molecular Mimicry; Multiple Sclerosis; Myelin; Myelin Basic Proteins; Neuraxis; Numbers; Organ; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Library; Peptides; Peripheral; Physiological; Play; Pliability; Predisposition; Principal Investigator; Proliferating; Relapsing-Remitting Multiple Sclerosis; Reporting; Role; Self Tolerance; Specificity; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Viral Genome; autoreactive T cell; central nervous system demyelinating disorder; combinatorial; disability; disorder control; insight; nervous system disorder; peripheral blood; programs; response; tool; young adult

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS) affecting primarily young adults in their most productive age, and therefore causing a significant disability. While its etiology remains elusive, most evidence supports the autoimmune pathogenesis of the disease. According to this hypothesis, the activation of autoreactive T-cells is a central event in the development of autoimmune response in MS. The objective of this proposal is to examine molecular events involved in the initiation of autoimmune response in MS. Recent studies have reported an unexpectedly high degree of T-cell receptor (TCR) degeneracy and molecular mimicry as a frequent phenomenon that might play a role in the initiation of autoimmune response in MS. MHC DR2-biased combinatorial peptide libraries are developed as a tool to characterize degenerate T-cells. As auto-antigens are predominantly weak TCR ligands, we propose that myelin-reactive T-cells may be over-represented among the cells with a degenerate TCR. Myelin basic protein (MBP)-specific T-cells exhibit decreased CD28 co-stimulatory requirements in MS patients when compared to healthy controls. We hypothesize that dysregulation of co-stimulatory pathways play a role in the initial activation, prolonged survival, and the expansion of autoreactive cells in MS. Co-stimulation-independent activation might be particularly relevant for the autoantigen recognition within the CNS, as local inflammatory environment enhances autoantigen presentation even in the absence of co-stimulatory molecules on the resident antigen presenting cells. We plan to achieve our objective by pursuing the following Specific Aims: 1) Determine the frequency and TCR repertoire of T-cell clonotypes with a high degree of TCR flexibility. 2) Define co-stimulation requirements for the activation and growth characteristics of T-cells with flexible TCR in RR MS patients and OND controls. 3) Identify mechanisms by which the inflammatory environment induces the autoreactive T-cell activation. The information provided by these studies may yield important insights into the physiologic and pathologic role of the autoreactive T cells, and characterize structurally and functionally the specific targets for the new therapies of MS.

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性自身免疫性脱髓鞘疾病，主要影响处于最具生产力年龄的年轻人，因此导致严重的残疾。虽然其病因尚不明确，但大多数证据支持该疾病的自身免疫发病机制。根据这个假设，自体反应性t细胞的激活是多发性硬化症自身免疫反应发展的中心事件，本提案的目的是研究与多发性硬化症自身免疫反应启动有关的分子事件。最近的研究报道，t细胞受体（TCR）的高度退化和分子模仿是一种常见现象，可能在多发性硬化症自身免疫反应的启动中发挥作用一种表征退化t细胞的工具。由于自身抗原主要是弱TCR配体，我们提出髓磷脂反应性t细胞可能在退化的TCR细胞中过度代表。与健康对照相比，MS患者髓鞘碱性蛋白（MBP）特异性t细胞表现出CD28共刺激需求降低。我们假设，在ms中，共刺激通路的失调在初始激活、生存期延长和自身反应细胞的扩增中发挥了作用，共刺激非依赖性激活可能与中枢神经系统内的自身抗原识别特别相关，因为局部炎症环境增强了自身抗原呈递，即使在驻留的抗原呈递细胞上没有共刺激分子。我们计划通过追求以下具体目标来实现我们的目标：1)确定具有高度TCR灵活性的t细胞克隆型的频率和TCR库。2)明确RR MS患者和OND对照中具有柔性TCR的t细胞活化和生长特性的共刺激要求。3)确定炎症环境诱导自身反应性t细胞活化的机制。这些研究提供的信息可能对自身反应性T细胞的生理和病理作用产生重要的见解，并在结构和功能上表征MS新疗法的特定靶点。

项目成果

Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis.

深入了解阿仑单抗治疗多发性硬化症的疗效机制。

• 发表时间: 2013
• 期刊: Journal of clinical & cellular immunology
• 作者: Freedman,MarkS;Kaplan,JohanneM;Markovic-Plese,Silva
• 通讯作者: Markovic-Plese,Silva

Oligoclonal myelin-reactive T-cell infiltrates derived from multiple sclerosis lesions are enriched in Th17 cells.

• DOI: 10.1016/j.clim.2008.08.030
• 发表时间: 2009-03
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Montes M;Zhang X;Berthelot L;Laplaud DA;Brouard S;Jin J;Rogan S;Armao D;Jewells V;Soulillou JP;Markovic-Plese S
• 通讯作者: Markovic-Plese S

Degenerate T-cell receptor recognition, autoreactive cells, and the autoimmune response in multiple sclerosis.

多发性硬化症中的退化 T 细胞受体识别、自身反应性细胞和自身免疫反应。

• DOI: 10.1177/1073858409332404
• 发表时间: 2009
• 期刊: The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
• 作者: Markovic-Plese,Silva